1. Field of the Invention
The present invention relates to novel processes for preparing various cephalosporins. The present invention further relates to novel intermediates useful for preparing cephalosporins.
2. Discussion of the Background
Numerous cephalosporins of formula (I)
characterized by the presence of a 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic chain in the 2 position of 7-ACA, and its derivatives of formula (II)
are known in which R2 can have various meanings including —CH2OCOCH3 in the case of 7-ACA, the cefotaxime nucleus, or
in the case of 7-ACT, the ceftriaxone nucleus, or
in the case of Furaca, the ceftiofur nucleus.
Each of these cephalosporins, including those having a different meaning of R1 and R2, was independently invented and synthesized with its own synthesis method, so that initially there was no common method suitable for producing all cephalosporins having the 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic chain.
U.S. Pat. No. 5,583,216 discloses a process for inserting the aforesaid chain into 7-ACA and its derivatives for the production of any cephalosporin included in the aforesaid group. However, the process disclosed in U.S. Pat. No. 5,583,216 cannot be applied industrially for producing cephalosporins.
U.S. Pat. No. 6,458,949 discloses the intermediate of formula (A)
in which X is Cl or Br, and its use for preparing ceftiofur by cyclization with thiourea.
This intermediate is always precipitated in an acid form from a solution in methylene chloride at a temperature of 2 to 5° C., collected by filtration, washed with cold water (5° C.) and then with methylene chloride. In view of the fact that the precipitate originates from a solution in methylene chloride, according to the usual technique it would have been logical to expect the first wash to have been effected with the same solvent, the water wash being effected only later. This reversal of the wash order and the use of cold water are therefore not random, but point to the fact that the intermediate does not possess great stability and that the water-soluble acid impurities which impregnate the solid just filtered off must be rapidly removed. In addition, the intermediate disclosed in U.S. Pat. No. 6,458,949, again in acid form, is dried before subsequent cyclization with thiourea, as this reaction is carried out in water-tetrahydrofuran and it is advisable to remove methylene chloride residues. Moreover the maximum obtainable yield is only 75%.
U.S. Pat. No. 6,552,186 discloses a compound of formula (IV)
in which X is halogen, R3 is trialkylsilyl and R2 is
or
This compound may be reacted with silylated thiourea to provide a compound of formula (I) in which R1 and R2 have the aforesaid meanings and which on subsequent hydrolysis gives the compound having the same formula (I) but in which R1 is H and R2 is as afore-stated, i.e., ceftriaxone.
Thus, U.S. Pat. No. 6,522,186 discloses a compound of formula (IV) in which R3 is trialkylsilyl. The corresponding derivative in which R3 is H, however, had already been disclosed in U.S. Pat. No. 4,458,072 as an amorphous product (see, column 16, line 49) without any indication of the yield, by a laborious process using a precipitating agent such as petroleum ether. The disclosed method is certainly unsuitable for industrial use. Moreover, U.S. Pat. No. 6,552,186 says nothing about yields, as the disclosed process comprises direct formation of the silylated product of formula (IV) and subsequent reaction with silylated thiourea to give silylated ceftriaxone. The final step to obtain ceftriaxone disodium salt takes place by known methods. However, overall total process yields are not given.
U.S. Pat. No. 6,458,949 discloses a process by which Furaca is silylated and then reacted with a compound of formula (III)
in which X is Cl or Br and Y is Cl, or —O—CH═N+(CH3)2Cl− to isolate an afore-stated compound of formula (A), in which X is Cl or Br and the carboxyl is free, non-salified and non-esterified. When reacted with thiourea in a partly aqueous solvent, this intermediate produces ceftiofur.
Compounds of formula (III) have been known for some time. For example, GB 2,012,276 describes in example 5 the preparation of a compound of formula (III) in which the methoxyimino group is substituted by the ethoxyimino group, X is Br and Y is Cl, by reacting the corresponding acid having the same formula (III) but in which X is Br and Y is OH, with PCl5 in a dichloromethane solution. According to example 13 of GB 2,012,276,7-(4-chloro-3-oxo-2-methoxyiminobutyryl-amino)cephalosporanic acid is subsequently reacted with thiourea to give a sodium salt of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido)cephalosporanic acid, this being cefotaxime,
EP 30294 (page 4, lines 36–37 and 40–45), U.S. Pat. No. 6,384,215 (column 3, lines 19–20) and U.S. Pat. No. 6,458,949 (column 4, line 1; column 5, line 2 and lines 47–48) also describe the preparation of compounds having a structure similar to that of formula (III).
It is therefore apparent that compounds of formula (III) in activated form, able to react with a compound of formula (II) silylated at the carboxyl, can be prepared for example as chlorides by reaction with PCl5 or other chlorinating agents, such as POCl3 and DMF, in dichloromethane.
However, there remains a need for new methods for producing cephalosporins. There also remains a need for new intermediates which are useful for producing cephalosporins.